2-disubstituted cyclohexenyl and cyclohexyl antimicrobial agents

The invention relates to cyclohexenyl antibacterial compounds of the formula I: ##STR1## and pharmaceutical compositions containing the compounds, methods for their production and use.

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Claims

1. A method of treating bacterial infections in mammals which comprises administering to said mammal an antibacterially effective amount of a compound having activity as a histidine protein kinase inhibitor selected from those of the Formula I: ##STR71## wherein: R.sub.1 is selected from branched or unbranched (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6) hydroxyalkyl, and a moiety of the formula: ##STR72## wherein: p is an integer from 0-6;

and R.sub.3, R.sub.4 and R.sub.5 are independently selected from hydrogen, halo, (C.sub.1 -C.sub.4) alkyl, (C.sub.1 -C.sub.4) alkoxy, hydroxy, hydroxyalkyl, amino, (C.sub.1 -C.sub.4) alkylamino, and nitro;
n is an integer from 1-6;
q is an integer from 0-2;
X is selected from O and S;
R.sub.2 is selected from phenyl and a heterocyclic moiety wherein the heterocyclic moiety is a monocyclic heterocyclic group having 5 or 6 ring atoms and 1-4 nitrogen, oxygen, or sulfur atoms and is saturated or unsaturated, and wherein the phenyl or heterocyclic moiety is substituted with amino, moieties of the formula: ##STR73## carboxy, carboxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylcarboxy, or a moiety of the formula: ##STR74## and, optionally, 1-3 substituents selected from oxo, halo, trifluoromethyl, hydroxy, -(C.sub.1 -C.sub.6) alkyl and (C.sub.1 -C.sub.6) alkoxy;
wherein R.sub.6 is selected from hydrogen and (C.sub.1 -C.sub.6)alkyl;
R.sub.7 is selected from hydrogen, (C.sub.1 -C.sub.6 ) alkyl, (C.sub.3 -C.sub.6) cycloalkyl, (C.sub.1 -C.sub.6) hydroxyalkyl, (C.sub.1 -C.sub.6)acyl, a moiety of the formula: ##STR75## and a moiety of the formula
R.sub.8 is selected from amino, amino(C.sub.1 -C.sub.6)alkyl, amino((C.sub.1 -C.sub.6)alkyl).sub.2, an aryl group and a heterocyclic group wherein the aryl group is a monocyclic or bicyclic aromatic hydrocarbon group having from 6 to 10 carbon atoms and the heterocyclic group is a monocyclic or bicyclic group of 4-10 ring atoms wherein the heteroatom or heteroatoms are selected from 1-4 oxygen, nitrogen or sulfur atoms and each ring of the heterocycle is composed of 4-6 atoms and is saturated or unsaturated; and the pharmaceutically acceptable salts thereof.

2. A method according to claim 1 wherein R.sub.1 is selected from branched or unbranched (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) hydroxyalkyl, and a moiety of the formula: ##STR76## wherein p is an integer from 0-6;

and R.sub.3, R.sub.4 and R.sub.5 are independently selected from hydrogen, halo, (C.sub.1 -C.sub.4) alkyl, and (C.sub.1 -C.sub.4) alkoxy;
n is an integer from 1-3;
X is O or S;
R.sub.2 is selected from phenyl, pyrimidine, pyrimidone and pyrazole and R.sub.2 is substituted with amino, moieties of the formula; ##STR77## carboxy, (C.sub.1 -C.sub.6)alkylcarboxy, carboxy(C.sub.1 -C.sub.6)alkyl, and a moiety of the formula: ##STR78## and, optionally 1-3 substituents selected from oxo, halo, trifluoromethyl, hydroxy, -(C.sub.1 -C.sub.6)alkyl, and (C.sub.1 -C.sub.6) alkoxy;
wherein R.sub.6 is selected from hydrogen and (C.sub.1 -C.sub.6)alkyl; and R.sub.7 is selected from hydrogen, (C.sub.1 -C.sub.6) alkyl, (C.sub.4 -C.sub.6) cycloalkyl, (C.sub.1 -C.sub.6) hydroxyalkyl, a moiety of the formula: ##STR79## and a moiety of the formula:
and the pharmaceutically acceptable salts thereof.

3. A compound of the Formula I: ##STR80## wherein: R1 is benzyl optionally substituted with one to three substituents independently selected from halo, (C.sub.1 -C.sub.4)alkyl, and (C.sub.1 -C.sub.4)alkoxy;

n is an integer from 1-3;
X is selected from O and S;
q is an integer from 0-2;
R.sub.2 is selected from phenyl, pyrimidine, pyrimidone and pyrazole and R.sub.2 is substituted with amino, moieties of the formula; ##STR81## carboxy, (C.sub.1 -C.sub.6)alkylcarboxy, carboxy(C.sub.1 -C.sub.6)alkyl, or a moiety of the formula: ##STR82## and, optionally 1-3 substituents selected from oxo, halo, trifluoromethyl, hydroxy, -(C.sub.1 -C.sub.6)alkyl, and (C.sub.1 -C.sub.6) alkoxy;
wherein R.sub.6 is selected from hydrogen and (C.sub.1 -C.sub.6)alkyl; and R.sub.7 is selected from hydrogen, (C.sub.1 -C.sub.6) alkyl, (C.sub.4 -C.sub.6) cycloalkyl, (C.sub.1 -C.sub.6) hydroxyalkyl, a moiety of the formula: ##STR83## and a moiety of the formula:
wherein m is an integer from 1-4; and
R8 is selected from amino, amino(C.sub.1 -C.sub.6)alkyl and phenyl, benzyl, pyrrolidine, morpholine, and indole;
and the pharmaceutically acceptable salts thereof.

4. A compound according to claim 3 wherein:

X is oxygen,
R.sub.2 is a moiety selected from those of the formulae: ##STR84## R.sub.6 and R.sub.7 are both hydrogen and R.sub.1, and n are as defined in claim 3.

12. A pharmaceutical composition for treating bacterial infections comprising an effective amount of a compound selected from claim 1 in association with a pharmaceutically acceptable carrier.

13. A pharmaceutical composition for treating bacterial infections comprising an effective amount of a compound selected from claim 2, in association with a pharmaceutically acceptable carrier.

14. A pharmaceutical composition for treating bacterial infections comprising an effective amount of a compound selected from claim 3 in association with a pharmaceutically acceptable carrier.

15. A pharmaceutical composition for treating bacterial infections comprising an effective amount of a compound selected from claim 4 in association with a pharmaceutically acceptable carrier.

16. A method of treating bacterial infections in mammals which comprises administering to said mammal an antibacterially effective amount of a compound selected from those of claim 3.

17. A method of treating bacterial infections in mammals which comprises administering to said mammal an antibacterially effective amount of a compound selected from those of claim 4.

Referenced Cited
U.S. Patent Documents
5290814 March 1, 1994 Jackson et al.
Foreign Patent Documents
WO 9115495 October 1991 EPX
Other references
  • Mahan, M. J., J. M. Slauch, and J. J. Mekalanos, Science, 259, 686-688 (1993). S. Roychoudhury et al., Proc. Natl. Acad. Sci., 90, 965-969 (1993) Inhibitors of Two-component Signal Transduction Systems: Inhibition of Alginate Gene Activation in Pseudomonas Aeruginosa. International Search Report--International Application No. PCT/US96/10357--International Filing Date Jun. 18, 1996. Chem. Phar. Bull. (1982), 30(10), 3601-16, XP002024094 p.3611, Line 7-Line 13 (Sohda et. al.). J. Biol. Chem. (1992), 267(22), 15511-15, XP002024096, Huang, Jiamnin et al. Database WPI, Section Ch, Week 9631 Derwent Publications Ltd., London, GB; Class B03, AN 96-306532 XP002024098.
Patent History
Patent number: 5753715
Type: Grant
Filed: Jun 2, 1995
Date of Patent: May 19, 1998
Assignee: Ortho Pharmaceutical Corporation (Raritan, NJ)
Inventors: Robert H. Chen (Belle Mead, NJ), Maud Urbanski (Belle Mead, NJ), Min Xiang (Bridgewater, NJ), John Francis Barrett (High Bridge, NJ)
Primary Examiner: Peter O'Sullivan
Attorney: Kenneth J. Dow
Application Number: 8/459,447
Classifications
Current U.S. Class: The Aryl Ring Or Aryl Ring System And Amino Nitrogen Are Bonded Directly To The Same Acylic Carbon, Which Carbon Additionally Has Only Hydrogen Or Acyclic Hydrocarbyl Substituents Bonded Directly Thereto (514/655); 514/2378; Chalcogen Bonded Directly To Pyrimidine At 2-position (514/274); Chalcogen Bonded Indirectly To The Five-membered Hetero Ring By Acyclic Nonionic Bonding (514/428); Carboxy Or Salt Thereof Only Attached Indirectly To The Benzene Ring (514/570); Sulfur In R (514/618); Nitrogen In R (514/619); Guanidines (i.e., N=c(-n)-n) (514/634); The Chain Consists Of Two Or More Carbons Which Are Unsubtituted Or Have Acyclic Hydrocarbyl Substituents Only (514/654); Nitrogen Attached Directly Or Indirectly To Morpholine Ring By Nonionic Bonding (544/159); Nitrogen Attached Directed Or Indirectly To Morpholine Ring By Nonionic Bonding (544/162); Nitrogen Attached Directly Or Indirectly To The Diazine Ring By Nonionic Bonding (544/311); The Nitrogen Is In A Substituent Attached To The Ring Nitrogen Of The Five Membered Hetero Ring (548/569); Carboxyl, Or Salt Thereof, Bonded Directly To A Ring (562/432); Carboxyl, Or Salt Thereof, Bonded Directly To A Ring (562/473); Sulfur In Substituent Q (564/162); Plural Rings In Substituent Q (564/171); Benzene Ring Containing (564/237); The Chain Contains Nitrogen Between The Aryl Ring Or Ring System And Amino Nitrogen (564/367); Ethylene Diamines (564/368); Mono Ethylene Diamines (564/369); Methylene Diamines (564/371); The Chain Consists Of Two Or More Carbons Which Are Unsubstituted Or Have Acyclic Hydrocarbyl Substituents Only (564/374)
International Classification: A61K 31165; A61K 31135; A61K 3117; A61K 3119;